High-density optical tomography of cerebral blood flow and metabolism in small animals

摘要 许多临床情况，包括中风，使大脑暴露于脑血流不足(CBF)，而不是 维持正常的大脑代谢耗氧速率(CMRO2)要求，从而导致 脑缺血/低氧应激和神经疾病。有效的干预措施取决于 CBF/CMRO2改善，最终神经恢复。啮齿动物(老鼠和大鼠)占95% 研究动物。然而，神经科学对啮齿动物模型的研究的一个主要限制是缺乏 用于连续和纵向监测CBF和CMRO2的负担得起的无创性成像技术 变种。大型成像设备(例如，CT、PET和MRI)需要昂贵的仪器，而且难度很大 用于纵向监测。便携、廉价的光学/超声技术极大地扩大了选择范围 对于连续的大脑监测，尽管大多数系统缺乏高时间-空间分辨率的组合， 视野开阔，深入大脑的深度适中。此外，目前还没有可用的 这些技术可以同时对脑血流量、脑组织氧饱和度(StO2)和CMRO2进行成像。至 克服这些限制，肯塔基大学(英国)的研究人员开发出一种创新的 基于ccd/cmos的散斑对比漫相关层析成像(scDCT：美国专利9861319号)技术 为了适应非侵入性、非接触性、快速、高密度的脑血流分布的3D成像， 和人类新生儿。SCDCT虽然有效，但在传播和商业化方面并未得到优化 在成像性能方面(信噪比、时空分辨率、精确度、易用性)，以及 仪器成本和便携性。Bioptics Technology LLC(BOT)与英国合作，计划开发、 优化、验证经济实惠、便携、易于使用的多波长scDCT(MW- SCDCT)技术，用于重复、纵向成像啮齿动物体内的CBF、StO2和CMRO2分布。新的 将开发方法学和算法以实现近乎实时的、高密度的、3D成像 大脑功能。MW-scDCT将使用头部模拟模型进行严格测试和优化 已知的光学和血流动力学特性(目标1)。绝对测量的活体校准和评估 用MW-scDCT对照标准灌注磁共振成像和组织学检查 无笔划(目标2)。最后，优化的mw-scDCT设备将传播给几个神经科学 英国国内外的研究人员收集关于仪器适用性和用户体验的反馈。 根据这些选定的最终用户的初步反馈，我们预计将确定改进和改进 在持续的第二阶段研究中需要MW-scDCT来生产最佳的产品级设备 商业化。最终的用途将扩大到更大的动物模型和人类受试者。然而， 这个第一阶段的项目将从啮齿动物开始，因为使用小动物对 将该设备商业化，从而为临床水平设备的未来商业化铺平道路。

ABSTRACT Many clinical situations, including stroke, expose the brain to insufficient cerebral blood flow (CBF) that cannot maintain normal cerebral metabolic rate of oxygen consumption (CMRO2) requirements, thereby leading to cerebral ischemic/hypoxic stresses and neurological disorders. Effective interventions are dependent on the findings of CBF/CMRO2 improvement and eventually neural recovery. Rodents (mice and rats) make up 95% of research animals. However, one major limitation with neuroscience research in rodent models is lack of affordable noninvasive imaging technologies for continuous and longitudinal monitoring of CBF and CMRO2 variations. Large imaging modalities (e.g., CT, PET, and MRI) require expensive instrumentation, and are difficult to use for longitudinal monitoring. Portable, inexpensive optical/ultrasonic technologies greatly expand choices for continuous cerebral monitoring although most systems lack the combination of high tempo-spatial resolution, wide field-of-view, and proper penetration depth into deep brains. Moreover, none of currently available techniques enable simultaneous imaging of CBF, cerebral tissue oxygen saturation (StO2), and CMRO2. To overcome these limitations, researchers at University of Kentucky (UK) have developed an innovative CCD/CMOS based speckle contrast diffuse correlation tomography (scDCT: US Patent #9861319) technique to accommodate noninvasive, noncontact, fast, high-density 3D imaging of CBF distributions in mice, rats, piglets, and human neonates. While effective, scDCT has not been optimized for dissemination and commercialization in terms of imaging performance (signal-to-noise ratio, temporal-spatial resolution, accuracy, easy-to-use), and instrument cost and portability. In collaboration with UK, Bioptics Technology LLC (BOT) proposes to develop, optimize, validate, and commercialize an affordable, portable, easy-to-use, multi-wavelength scDCT (MW- scDCT) technique for repeated, longitudinal imaging of CBF, StO2, and CMRO2 distributions in rodents. New methodologies and algorithms will be developed to achieve a nearly real-time, high-density, 3D imaging of cerebral function. The MW-scDCT will be rigorously tested and optimized using head-simulating phantoms with known optical and hemodynamic properties (Aim 1). In vivo calibration and evaluation of absolute measurements with MW-scDCT will be conducted against standard perfusion MRI and histological examination in rats with or without stroke (Aim 2). Finally, optimized MW-scDCT devices will be disseminated to several neuroscience researchers inside and outside UK to collect feedback regarding instrument applicability and user experience. With preliminary feedback from these selected end-users, we expect to identify refinements and improvements needed for the MW-scDCT in a continued Phase-II study to produce an optimal product-level device for commercialization. The ultimate use will be expanded to larger animal models and human subjects. However, this Phase-I project will begin with rodents as using small animals is easier, more economical and efficient for commercializing the device, thereby paving the way for future commercialization of clinical-level devices.